Summary Post-traumatic stress disorder (PTSD) is a debilitating neuropsychological disorder that develops as a result of exposure to physical or psychological trauma. Emerging evidence suggests that PTSD is a strong predictor of cardiovascular disease (CVD). Recent clinical studies suggest that blockade of the renin-angiotensin system (RAS)?crucial to blood pressure control and fluid homeostasis?reduces the severity of PTSD symptoms. We have also demonstrated in a preclinical mouse model of PTSD (Pavlovian fear conditioning) that angiotensin type 1 receptor (AT1R) inhibition attenuates conditioned fear responses and facilitates the extinction of conditioned fear. Both AT1Rs and angiotensin type 2 receptors (AT2Rs) are expressed in the amygdala, a brain region critical for fear learning and extinction. Whether different brains AT receptor subtypes play a role in stress disorders such as PTSD is largely unknown, as is their impact on cardiovascular dysfunction in fear. Our preliminary studies suggest, however, that activation and inhibition of brain AT2Rs have opposing effects on the expression of fear memory in a preclinical mouse model of PTSD. Utilizing a multi-disciplinary approach that combines physiological, molecular, analytical and behavioral neuroscience, this proposal will investigate the role of endogenous brain angiotensin II, its receptors (AT1R and AT2R) and downstream signaling pathways in fear memory and cardiovascular events associated with conditioned fear. Our working hypothesis is that the expression and activity of brain angiotensin II and its receptors (AT1R / AT2R) are differentially and dynamically regulated during the consolidation and recall of fear memory, and that these changes contribute to the balance of excitatory (?fear-on?) and inhibitory (?fear-off?) signals required for the storage and retrieval of conditioned fear memories. The goals of this proposal are two-fold: (1) Identify signaling pathways and gene networks that are both regulated by brain AT1R/AT2R activation and implicated in the excitatory and inhibitory signaling necessary and sufficient for fear learning and retrieval; (2) Determine the spatio-temporal contributions of AT1Rs and AT2Rs in key limbic and hypothalamic structures on the expression of conditioned fear memories and cardiovascular alterations. We have 2 specific aims. Specific Aim 1: To demonstrate that angiotensin II-induced activation of brain AT1Rs is necessary and required for the maintenance and reconsolidation of fear memory and the conditioned cardiovascular responses. Specific Aim 2: To demonstrate that activation of brain AT2Rs both stimulates fear-off neurons and reduces fear memory and adverse cardiovascular changes during fear conditioning. These studies will further elucidate the mechanism(s) by which the renin-angiotensin system acts as an important and novel mediator of PTSD pathology, and will provide new targets and opportunities for pharmacological interventions in PTSD and PTSD-related CVD co-morbidity.